At Yale, Rigorous Research Sets Stroke Treatments Up for Success

1 in 4.

On a Friday evening in 2023, those suddenly became Gillian Goldrich’s odds of returning to her old life. During dinner, Goldrich’s husband noticed that she was having trouble moving her spoon to her mouth.

“One minute, I was having dinner, I was perfectly fine,” Goldrich says. “Then my husband said, ‘You’re having a stroke, don’t move, I’m calling 911.’”

Goldrich, then 63 years old, was having an ischemic stroke—a clot had lodged in one of the primary arteries supplying blood flow to her brain. Within minutes, she had begun to exhibit the hallmark indicators of a stroke, often remembered using the mnemonic “Act F.A.S.T.”: Her face had begun to droop, her arm wasn’t functioning properly, and her speech became slurred and abnormal. The T is for “time” and the need to act immediately.

Goldrich had been in excellent health. She ate well and exercised regularly. Just months before the incident, she’d been told by a physician that her chances of having a stroke were 1.3%. Afterwards, her chances of returning to her pre-stroke function were 1 in 4.

Those odds may seem small, but they’re actually quite promising compared to what they would have been decades ago. If Goldrich had suffered her stroke even just 20 years earlier, she likely would have dealt with significant physical and mental impairments for the rest of her life.

“It’s amazing that for every four patients we treat, we bring one patient back to how they were before the stroke,” says Pooja Khatri, MD, chair of the Department of Neurology at Yale School of Medicine (YSM). “The field of stroke research has made incredible gains in the treatment landscape. But the fact is 75% of patients remain disabled and about half need help with their activities of daily living.”

Medications that protect the brain immediately after stroke—called acute treatments—would help bridge that gap, but developing those has been challenging, says Kevin Sheth, MD, professor of neurology and of neurosurgery at YSM.

“There’s never been a brain-targeted acute stroke drug treatment—ever,” says Sheth, who is also a director of the Yale Center for Brain and Mind Health and vice chair for clinical and translational research in neurology and neurosurgery at YSM.

Sheth has been studying whether glyburide, a medication usually used to treat type 2 diabetes, can prevent or reduce swelling in the brain caused by a stroke. His research shows that glyburide improves outcomes in patients. But it’s one of very few treatments to have shown promise at this stage of study. While others have been encouraging in preclinical research, they haven’t worked in humans.

To address this issue, YSM researchers are focused on developing new treatments for stroke as well as systems that test treatments so rigorously they’re more likely to succeed in humans. To do this, they’re working with experts across the country who are together shifting stroke research culture and ensuring the coming decades see even greater improvements for patients.

In 2012, Lauren Sansing, MD, professor of neurology and vice chair of faculty affairs at YSM, attended a conference held by the National Institute of Neurological Disorders and Stroke (NINDS) where she and other experts tried to identify exactly why there were so few stroke treatments, and why new ones kept failing.

“The whole field had a reckoning,” says Sansing. “What are we doing wrong? Can we change how we’re testing potential therapeutics?”

One of the major hurdles identified was that that rodent models being used were not representative of the real patient population. Most of the preclinical animal work was done in young, male mice and rats without other comorbidities. But stroke is predominantly a disease of older age, is more likely to affect women, and often occurs alongside conditions such as diabetes and hypertension.

In response, the National Institutes of Health (NIH) created the Stroke Preclinical Assessment Network (SPAN) in 2019. Comprised of six participating sites and a coordinating center, SPAN applies a standardized protocol for the use of animals in stroke research. The network accepts applications from researchers and companies looking to have their acute stroke treatments rigorously screened. Selected candidates are then tested by each of the six sites, which cross-analyze each other’s results.

It’s essentially a clinical trial, but with animals, says Sansing, principal investigator of the SPAN site at Yale.

SPAN intentionally uses a variety of rodents—young, old, male, female, hyperglycemic, and hypertensive—meant to mimic real patient groups. Further, across the six sites, there’s bound to be variability between their rodent populations. Normally, all of this would be an issue for a controlled experiment. But in SPAN, it’s welcome.

“We wanted to move away from a model where a compound working in a single lab was enough to warrant a clinical trial,” says Sansing. “In SPAN, a compound has to get past all this variability across the network, and if it can still show a benefit, then that’s a drug that we should take to clinical trial.”

In the first round of SPAN’s testing, the sites tested six different compounds. One made it through: uric acid, which showed protective effects after stroke. The results were published in March in the journal Stroke, and the next step will be to test uric acid in clinical trials.

There’s also work to be done on the clinical side, says Khatri. Being nimbler and more efficient when it comes to clinical trials would mean more could be initiated and across larger scales. NIH StrokeNet, a clinical trial pipeline coordinated by the NIH and NINDS, is enabling just that.

“StrokeNet brings stable infrastructure that has allowed us to do more trials more quickly,” says Khatri, who has served as a co-director of the National Coordinating Center of NIH StrokeNet since 2013. “If researchers don’t have to recreate the machinery every time they do a trial, it allows them to get funded faster, get started faster, and recruit patients faster.”

Yale is one of the 27 StrokeNet regional coordinating centers that serve as a backbone for this network, and Sheth serves as principal investigator for Yale’s region. Researchers with trial proposals in any area of stroke research can bring their ideas to the network, which assists with developing the idea and submitting a formal grant application to the NIH. If funded, the network puts out a call to its approximately 500 affiliated hospitals to see which sites want to participate.

Because of StrokeNet, and through robust collaboration between YSM and the Yale New Haven Health System, Yale has been able to bring numerous clinical trial opportunities to patients, such as the ASPIRE trial, which investigates the use of blood thinners in hemorrhagic stroke patients, and the STEP trial, a platform which allows researchers to test multiple new interventions at the same time to determine which improve outcomes after strokes due to blocked arteries.

Sansing hopes that uric acid, the treatment that made it through SPAN’s first phase of preclinical testing, could move into clinical testing with STEP.

“If we can be really nimble and set up SPAN as a potential platform where we could get different therapies tested and then be able to sort of move things quickly into a clinical trial in STEP, we might be able to shorten this really long period from discovery to a positive clinical trial by years,” she says.

Exemplifying how these strategies are identifying exciting treatments really worthy of a clinical trial is work from Guido Falcone, MD, ScD, associate professor of neurology at YSM and director of clinical research in neurocritical care, neurology. Falcone studies genetic variants behind risk factors for stroke.

In a recent Annals of Neurology study, for instance, his lab linked genetic susceptibility to high blood pressure with higher rates of uncontrolled blood pressure and stroke, even when patients were on blood pressure treatment medications. In a study recently published in Neurology, Falcone’s research team found that genetic susceptibility to hyperlipidemia (high lipid levels) was associated with worse clinical trajectories for survivors of ischemic stroke.

He uses this type of information to “emulate” a real clinical trial.

“When you are testing a particular treatment, if there is human genetic support, the chances of clinical trial success go up significantly,” he says.

Falcone and his group used population genetics to show that, on average, individuals who are genetically predisposed to have lower lipid levels have a higher risk of having a hemorrhagic stroke, also known as a brain bleed. These results, coupled with evidence from other groups, constitutes the foundation of an ongoing clinical trial—supported by StrokeNet—to test if reducing the use of cholesterol-lowering medications after a brain bleed provides better patient outcomes.

For patients like Goldrich, this fast pace of research and easy access to clinical trials is going to make all the difference.

Upon arrival at Yale New Haven Hospital (YNHH), Goldrich was given the opportunity to receive a cutting-edge treatment by participating in the THUNDER trial, a study aimed at evaluating the safety and efficacy of a new device for removing clots.

Doctors ran a catheter through Goldrich’s groin and into her brain, where, with the device, surgeons quickly suctioned out her clot. The device applies suction intermittently, rather than continuously like currently used devices.

“If you’re able to remove a clot completely in one pass, patients tend to do better,” says Charles Matouk, MD, professor of neurosurgery at YSM and chief of neurovascular surgery at YNHH, who led the trial. “What the THUNDER trial explored was this idea that if you apply intermittent aspiration, you can increase its efficiency and do more in one pass.”

Not even a full day after her stroke, Goldrich was sitting up in bed and knitting. Today, she functions almost exactly as she did before her stroke, attending Zumba classes and going on daily walks.

“I can’t tell you how grateful I am for those doctors and the fact that they recognized that I would be one of the candidates for that study,” she says.

Goldrich realizes just how different her outcome could have been, and she’s motivated to help others, both by providing support and motivation to fellow stroke survivors in recovery groups, but also by continuing to participate in stroke research.

“I get into as many studies as I can to help the research and make things better for the next person,” she says.